Many drugs are not suitable for passive drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body, as for example, through intact skin. This concept is based upon basic principles of electrochemistry and is defined as electrically assisted transport, hereinafter referred to as "electrotransport". An electrochemical cell in its simplest form consists of two electrodes and associated half cell reactions, between which electrical current can flow. Electrical current flowing through the metal portion of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid phase is carried by ions (ionic conduction). In order for current to flow in an electrochemical cell, it is necessary for electrical charge to be transferred to chemical species in solution by means of oxidation and reduction charge transfer reactions at the electrode surfaces.
As electrical current flows, oxidation and reduction of some chemical species take place. A variety of electrochemical reactions can be utilized, and these fall into two classes. In one class, the electrode material participates in the charge transfer reaction; i.e., the electrode material is consumed or generated. In the other class, the electrode material behaves as a catalyst; i.e., the reduced and oxidized species exist in solution and the charge transfer reaction is catalyzed at the electrode surface. An example of the former is represented by: EQU Zn.revreaction.Zn.sup.+2 +2e.sup.-
or EQU Ag+Cl.sup.- .revreaction.AgCl+e.sup.-
where the forward reaction is the oxidation or anodic process and the reverse reaction is the reduction or cathodic process.
Examples of electrochemical reactions involving species independent of the electrode materials are the hydroquinone/quinone and the ferrous/ferric ion couples: EQU H.sub.2 Q.revreaction.Q+2H.sup.+ +2e.sup.-
and EQU Fe.sup.++ .revreaction.Fe.sup.+++ +e.sup.-
Again, the forward reaction is the anodic process and the reverse reaction is cathodic. These reactions are catalyzed by an appropriate conducting surface
When electrical charge is either generated or consumed at an electrode surface, ionic species must be transported to maintain electroneutrality throughout the system. Three physical processes contribute to this transport: passive diffusion, electromigration and convection.
The Nernst-Planck equation (1) expresses the flux for any particular chemical species, i, in the presence of an electrical field. The development of this equation is well known and explained in detail in electrochemistry texts such as J.S.Newman, Electrochemical Systems (Prentice-Hall, 1973) and A.J.Bard & L.R.Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980). Therefore, only pertinent conclusions will be presented here.
The Nerst-Planck equation (1) has three terms, one for each of the physical processes contributing to the mass transport. The first term describes the flux due to passive diffusion, which is proportional to the concentration gradient of species i. The second term describes the flux due to electromigration or electrodiffusion, where the driving force is the gradient of electrical potential. The third term describes the flux due to convection, where the mechanism of transport is the movement of material by bulk fluid flow which is determined by the magnitude and direction of the bulk fluid velocity vector. EQU J.sub.i =-D.sub.i .gradient.C.sub.i -z.sub.i F u.sub.i C.sub.i .gradient..PHI.+C.sub.i v (1)
where
J.sub.i =flux of species i (moles/cm.sup.2 -sec) PA1 D.sub.i =diffusion coefficient of i (cm.sup.2 /sec) PA1 .gradient.=the gradient operator PA1 C.sub.i =concentration of i PA1 z.sub.i =number of charges per molecule of i PA1 F=Faraday's constant (96,500 coulombs/mole of charge) PA1 u.sub.i =mobility of i (velocity/force) PA1 .PHI.=electrical potential (volts) PA1 v=velocity vector PA1 J.sub.i,x =flux of species i in the x direction PA1 E.sub.x =electrical field in the x direction; i.e., the negative of the electrical potential gradient PA1 v.sub.x =the x component of the velocity vector PA1 .epsilon.=electrical permitivity in the fluid phase PA1 .zeta.=zeta potential of the membrane PA1 .kappa.=conductivity of the fluid phase PA1 .mu.=viscosity of the fluid phase
Considering transport in only one direction of a rectilinear coordinate system, equation (1) may be simplified to: EQU J.sub.i,x =-(D.sub.i) (dC.sub.i /dx)+z.sub.i F u.sub.i C.sub.i E.sub.x +C.sub.i v.sub.x ( 2)
where
When an electrochemical half cell containing one or more drug species is placed upon the skin (the positive x-direction being perpendicular to the skin and directed out of the device and into the body), a concentration gradient will be established across the skin by virtue of the fact that the device contains a finite concentration of drug species and presumably, at least initially, the body contains a lower concentration of the species. Therefore, transport of material by passive diffusion will proceed.
If another electrode, electrically connected to the first electrode is placed on the skin, an electrical field may be imposed across the skin by applying a potential difference between these two electrodes. If the drug species exist in solution as charged species, then transport of material will proceed by electromigration. Additionally, a bulk fluid flow can exist with a net transfer of material from the patch into the body, when an electrical field is imposed across the skin. This process, called electroosmosis, can also result in the net flux of drug species from the patch into the body.
Equation (2) applies within each and every phase and the physical constants and extensive properties must be applicable to the phase of interest. In this manner, one form of equation (2) holds within the electrotransport patch where D.sub.i, C.sub.i, u.sub.i and so forth, are the diffusion coefficient, concentration, and mobility of species i within the patch materials. In the skin, another identical form of equation (2) holds except the diffusion coefficient, concentration and mobility of species i are now those within the skin. The extensive properties of these equations, such as the concentration and electric field, are linked at the interface by proportionality constants such as the partition coefficient and the ratio of dielectric constants, respectively.
As described above, three physical processes may contribute to the mass transport of a particular chemical species across the skin when an electrical field is imposed across the skin. It is the sum of the fluxes resulting from these three processes, passive diffusion, electromigration and bulk fluid flow resulting from electroosmosis, which define electrotransport.
Electrotransport is ideal for controlled delivery of substances having relatively low passive diffusion transport rates. In that instance, the first term of equation (1) would be very small in comparison to the second electromigration and/or third convective (electroosmotic) terms. For such a substance, drug delivery can be controlled by the electrical current applied through the patch.
When current is passed between two electrodes placed on the skin, the charge carriers through the skin and body are ions; for example, the ionized drug and endogenous ions such as sodium, potassium, and chloride ions. The total current density, i, is the sum of the current densities carried by each charged species, i.sub.j, as is shown by the following equation: ##EQU1## where E is the magnitude of the electrical field. The fraction of current carried by any particular species is given by the ratio of i.sub.j to i and this ratio, t.sub.j, is called the transference number of species j and is expressed as: EQU t.sub.j =i.sub.j /i=(.vertline.z.sub.j .vertline. u.sub.j C.sub.j)/(.SIGMA..vertline.z.sub.k .vertline. u.sub.k C.sub.k)(4)
The transference number indicates the fraction of the current carried by the drug ion in the skin. This is the most difficult factor to predict because it depends upon many physical, chemical and biological factors; for example, the total concentration of drug and its mobility in the skin, the local pH that determines the fraction of ionized drug, and the mobilities and concentrations of other ions.
An electric field not only gives rise to electromigration, it can also induce an electroosmotic flow. Electroosmosis is defined as the volume flow of solvent through a charged membrane when an electrical field is imposed across that membrane. The skin itself behaves as a charged membrane with its isoelectric point being within the range of about pH.sub.iso of 4.0-5.5, meaning that the skin is positively charged below this point and negatively charged above. When solvent is transported, charged or uncharged solutes contained therein may also be transported, including macromolecules and polypeptides. In this manner, electroosmosis can be used for the transdermal transport of neutral, as well as charged compounds.
The electroosmotic flow is generated by electromigration of ions which exist in the diffuse double layer next to the surface of a charged membrane. These ions entrain bulk solvent resulting in a flow. Equation (5) shows that the average velocity, &lt;v&gt;, through a pore is proportional to the total current, I, flowing through that pore: EQU &lt;v&gt;=(.epsilon..zeta.I ) / (.kappa..mu.) (5)
where
Equations (1) through (5) demonstrate that when passive diffusion is a minor component to the flux of a species and when the only convective flux is that resulting from electroosmosis, the flux of any particular species is directly proportional to the current density. Therefore, under these conditions control of the current density can be used to control the flux of drug through skin.
In applying these principles to drug delivery, the drug being delivered can be electrically assisted into the skin. There are a number of categories in which drug delivery systems utilizing electrotransport principles can offer major therapeutic advantages. See P.Tyle & B.Kari, "Iontophoretic Devices", in DRUG DELIVERY DEVICES, pp. 421-454 (1988).
Even though the concept of electrotransport in drug delivery is known, there is a continuing need to develop systems with improved control of the drug delivery rate, along with overcoming problems associated with known electrotransport devices, such as size, reliability, comfort to the wearer, composition and programmability.